Estrogenic compounds and animal growth promoters



United States Patent ABSTRACT OF THE DISCLOSURE R-O (I) on,

(i-o-oH-(o1-r,

\A Hzh Where A is a radical selected from the group consisting of -CH=CH- and CH -CH R is selected from the group consisting of hydrogen, lower alkyl and benZyl, and X is selected from the group consisting of nitroand amino-; and animal feeds containing growth promoting amounts thereof.

CHzX

This application is a continuation-in-part of application Ser. No. 561,401, filed June 29, 1966, now abandoned.

This present invention relates to new compounds and an object of the present invention is to provide compounds which exhibit estrogenic activity or aid in increasing the rate of growth in meat-producing animals, e.g., cattle, lamb and swine.

The compounds of this invention are illustrated by the formula:

H CHs where A is CH -CH or OH=CH-; R is hydrogen, substituted or unsubstituted alkyl, e.g. lower alkyl such as methyl, ethyl, hexyl, etc., or aralkyl, e.g. benzyl; and X is nitroor amino-.

The compounds of the present invention can be produced from the compound:

on E

CH=CH (CH2) 3 hereinafter referred to as the fermentation estrogenic substance (F.E.S.) by reaction with nitromethane in the presence of, for example, dibutylamine catalyst. The hydroxyl groups on the benzene ring of F.E.S. can be converted to ethers, e.g., methyl ethers, as taught in US Patent 3,239,342. Benzyl ethers of PBS. are described in copending application Ser. No. 532,113, filed Mar. 7, 1966, now abandoned, and application Ser. No. 620,259, filed Mar. 3, 1967, and dihydro F.E.S. where A is -CH -CH is described in US, Patent 3,239,354. In producing compounds where X is amino, the nitro compound is first produced and then reduced.

The compounds can be administered to animals by any suitable method including oral and parenteral administrations. For example, the compound can be blended with ordinary feed containing nutritional values in an amount sufficient to produce the desired rate of growth and can thus be ted directly to the animals, or the compound can be suspended in a suitable injection suspension medium such as peanut oil and injected parenterally. The amount of compound fed to an animal, of course, varies depending upon the animal, desired rate of growth and the like.

When the new compounds are to be administered in feeds, an animal feed composition may be prepared containing the usual nutritionally-balanced quantities of carbohydrates, proteins, vitamins and minerals, together with the compound of the present invention. Some of these usual dietary elements are grains, such as ground grain and grain by-products; animal protein substances, such as those found in fish meal and meat scraps, vegetable proteins like soybean oil meal or peanut oil meal; vitaminaceous materials, e.g., vitamin A and D mixtures; riboflavin supplements and other vitamin B complex members; and bone meal and limestone to provide minerals. A type of conventional feed material for use with cattle includes alfalfa hay and ground corn cobs together with supplementary vitaminaceous substances if desired.

The following examples serve to illustrate the invention.

Example I To a mixture of 1 mole of F.E.S., there are added 126 grams (2 moles) of nitromethane and 70 grams of dilbutylamine catalyst. The mixture is refluxed for 30 hours after which it is poured into sufiicient 6 N hydrochloric acid to neutralize the dibutylamine. This operation is conducted with cooling so that the temperature does not rise above 50 C.

The two layers are separated and the non-aqueous layer is subjected to distillation at 25 torr. About 40% of the initial F.E.S. is converted to the desired product.

OH (I) CH3 l The unconverted F.E.S. and the product are separated by column chromatography.

The dibutylamine in the aqueous layer is recovered, by addition of caustic to neutralize the HCl followed by distillation.

Example II Dihydro F.E.S., F.E.S.-2,4-dimethylether, F.E.S.-2- methyl ether, F.E.S-4-benzylether and dihydro PBS-2,4- diethylether are reacted according to the procedure of Example I to produce the corresponding nitromethylsubstituted compound.

Example III Two moles of the product of Example I are reduced with 750 grams of cast iron turnings. The cast iron turnings are placed with 1000 cc. of water in a three necked flask fitted with a stirrer, a thermometer and an eificient condenser. One hundred twenty cc. of concentrated HCl are added and the mixture heated to C. while stirring. The product of Example I (2 moles) is added along with 300 cc. of cone. HCl intermittently in small amounts while maintaining the temperature at 100103 C. After all materials are added, the temperature is maintained at 100 C. for 2 hours and the mixture is filtered to yield C I-IzN H2 Example IV The nitromethyl-substituted F.E.S. compounds of dihydro F.E.S., F.E.S.-2,4-dimethylether, F.E.S-2-methylether, E.E.S.-4-:benzylether and dihydro F.E.S.-2,4-diethylether produced according to Example II are hydrogenated according to the procedure of Example 111 to produce the corresponding amino-substituted compound.

Example V Six head of cattle are fed a daily ration containing 5 to 20 grams of the compound of Example I per 100 pounds ration to improve their rate of growth.

Example VI Six head of cattle are fed a daily ration containing 5 to 20 grams of the compound of Example III per 100 pounds ration to improve their rate of growth.

The following are specific examples of animal feed compositions of this invention useful for increasing the rate of growth and feed emciency of young animals to market weight.

Example VII For young beef cattle, i.e., calves to yearlings running to two years old, each animal is given 5 to 20 milligrams per day of the compound produced in Example I initirnately admixed in about 18 to 22 pounds per head per day of a complete pelleted ration for about 180 days. The complete pelleted ration includes in addition to the compound of Example I the following:

Barley percent 40-43 vMollasses dried beet pulp do 34.5-37.5 Alfalfa pellets do 8.0 Tallow do 2.5 Calcium carbonate do .30 Urea do .30 Phosphorus source do .40 Salt do .50 Molasses do 10.00 Trace mineral do 0.5 Vitamin A MMI.U./ton 2-4 Note-Milo or corn, for example, can be substituted for the barley.

The compound of Example I is admixed with the above ingredients in a stationary blender or a feed mix truck in the following amounts in grams per ton to provide an appropriate complete pelleted feed with dosage levels ranging from 5 to 90 milligrams per head per day.

Grams/ ton: Mg./ head/ day .5 5 1.0 2.0 4.0 40 8.0 80

These gram amounts are premixed with, for example, 10 pounds of soybean hulls prior to admixture with the other ingredients.

Example VIII For young swine, i.e., six-week old pigs to about 100- pound pigs, each animal is given 5 to 20 milligrams per day of the compound of Example III intimately admixed in about 1 /2 to 5 /2 pounds per head per day of a grower ration until it reaches a 'weight of about 100 pounds. When the swine weigh between 90 and 125 pounds the Grower, Finisher, percent percen Ground Yellow Corn Soybean Meal (44% protein)... Meat and Bone Scraps (50% prote Dehydrate Alfalfa Meal (17%) Steamed Bone Meal Ground Limestone Iodized Salt Vitamin, Antibiotic and Trace Mineral Premix.

The compound of Example III is admixed with the above ingredients in a blender in the following amounts in milligrams per pound to provide an appropriate feed with dosage levels ranging from 6 to 96 milligrams per head per day.

Mg./ pound Mg./ head/ day 2 6 4 12 8 24 16 48 32 96 Example IX For 4- to 10-month old lambs weighing 50 to 70 pounds, each animal is given 1 to 15 milligrams per day of the compound of Example I, intimately admixed in about 3 to 6 pounds per head per day of a complete ration for 30 to days. The complete ration includes in addition to the compound of Example I the following:

Pounds Finely ground corn cobs 630 Ground corn 600 Dehydrated alfalfa meal 300 Dried molasses Soybean meal (44% protein) 300 Dicalcium phosphate 14 Trace mineral salt 17 Premix vitamin, mineral and antibiotic 19 The compound of Example I is admixed with the above ingredients in a blender in the following amounts in milligrams per pound to provide an appropriate complete feed with dosage levels ranging from 1 to 15 mililgrams per head per day.

Mg./pound Mg./head/ day .5 2 1.0 4 1.5 6 2.0 8 2.5 10 3.75 15 Example X For broilers, i.e., day old to four week old chicks, a grower feed is prepared for feeding to the chicks for the first four weeks and a finisher feed is prepared for feeding the four-week-old chicks for the last five weeks until they reach market weight of two and a half to three pounds dressed. For each pound of weight gain, the chicks eat about 1.5 to 2 pounds of feed. Thus they eat about 1.5 pounds of feed during the first four weeks and about five pounds of feed during the next five weeks. During the course of this feeding schedule, each bird should receive a total of about 12 to 36 mililgrams of the compound of Example III in the grower and finisher feed Finisher Grower (1 (lbs.)

Ground Yellow Corn Soybean Meal (44% Protein). Protein) Dicalcium Iodized Sal Limestone Pregiix Vitamins Trace Minerals and Antibi- :)a where A is a radical selected from the group consisting of -CH=CH-- and CH -CH R is selected from the group consisting of hydrogen, lower alkyl and benzyl, and X is selected from the group consisting of nitroand amino-.

2. The compound of claim 1 where X is nitroand A is CH=CH.

3. The compound of claim 2 where R is hydrogen.

4. The compound of claim 1 where X is nitro and A is --CH CH 5. The compound of claim 4 where R is hydrogen.

6. The compound of claim 1 Where X is amino and A is -CH=CH-.

7. The compound of claim 6 where R is hydrogen.

8. The compound of claim 1 where A is amino and A is CH CH 9. The compound of claim 8 Where R is hydrogen.

10. An animal feed composition comprising a nutrient ration and a growth promoting amount of the compound of claim 1.

No references cited.

A. LOUIS MONACELL, Primary Examiner. H. H. KLARE III, Assistant Examiner. 

